While the literature provides little evidence that it is either safe or efficacious for this indication, Botulinum toxin A (BoNT/A) has received keen recent interest as a treatment option for patients with persistent myofascial temporomandibular muscle and joint disorder (TMJD). Were it shown to be safe and effective when injected into the masticatory muscles, it could prove invaluable to the many TMJD patients who do not respond to existing treatment modalities. Several studies have reported equivocal evidence of efficacy, but close inspection shows that those studies were either underpowered and/or poorly controlled. BoNT/A safety, on the other hand, has not been well assessed in TMJD patients, despite the fact that preclinical studies suggest profound changes in the morphology of the mandibular condyle and loss of alveolar bone following injection of the masticatory muscles. To address both of these issues, we propose a randomized, double-blind, placebo-controlled clinical trial (RCCT) with a one month run-in followed by two treatments spaced 3 months apart and a 3 month follow-up. Myofascial TMJD patients (51 per group) who meet Research Diagnostic Criteria will be randomly assigned to receive either BoNT/A or saline vehicle injections. After the second efficacy follow-up period, patients assigned to BoNT/A will be followed for an additional treatment cycle and 3 month follow-up period, to further assess bone-related changes. This clinical trial will determine the effect of single and repeated injections of BoNT/A into the masseter, temporalis and lateral pterygoid muscles on changes in (1) spontaneous and elicited pain intensity, (2) masticatory muscle function, and (3) density, volume and morphology of the mandible and maxilla in regions supporting the posterior teeth, as well as the mandibular condyle. The R34 planning period for this RCCT will be used to develop a full protocol and MOP, address regulatory issues, obtain IRB approval, plan for data safety monitoring, and finalize a detailed protocol for cone-beam CT based evaluation of bone-related changes indicating potential safety risks. This study not only satisfies NIDCR's mission to support innovative clinical research to improve craniofacial health, but it will also provide key information, regardless of the direction of the results, critical for evidence-based clinical practce. PUBLIC HEALTH RELEVANCE: Evidence that BoNT/A is either a safe or efficacious treatment option for myofascial TMJD is lacking. As such, use of BoNT/A for TMJD pain presents a potential public health issue. This study not only satisfies NIDCR's goal of supporting innovative clinical research to improve craniofacial health; it has also been designed to provide key information, regardless of the direction of the results, critical for evidence based clinical practce.